Hypoxia Converts Human Macrophages Into Triglyceride-Loaded Foam Cells

Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg, Sweden.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 09/2006; 26(8):1871-6. DOI: 10.1161/01.ATV.0000229665.78997.0b
Source: PubMed


Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells.
Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in beta-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of beta-oxidation, whereas the accumulation of triglycerides increased.
The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.

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Available from: Lillemor Mattsson Hultén, Oct 05, 2015
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    • "There are other factors which have been associated with an increase in LLAM formation. These include gastroesophageal reflux disease (GORD) [10] [11], hypoxia [12] and iatrogenic causes, whereby drugs such as amiodarone, fluoxetine, and gentamicin containing a cationic amphiphilic structure can induce cellular phospholiposis through a dose-dependent process involving the inhibition of lysosomal phospholipase activity and accumulation of lamellar bodies [13] [14]. In addition, macrophages have been shown to internalise and degrade surfactant lipids and surfactant protein A (SP-A) in vitro, suggesting a role for AMs in surfactant clearance [15]. "
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    ABSTRACT: The presence of lipids in alveolar macrophages (AMs) may impair their phagocytic response, and determine airway inflammation and obstruction. To determine the factors such as severity of asthma, chronic cough, airway inflammation and obesity that may influence the presence of lipids in lung macrophages. Bronchoalveolar lavage fluid (BALF) was obtained from 38 asthmatics (21 severe and 17 mild/moderate), 16 subjects with chronic cough and 11 healthy control subjects. The presence of lipids in macrophages was detected using an Oil-red-O stain and an index of lipid-laden macrophages (LLMI) was obtained. LLMI scores were higher in healthy subjects (median 48 [IQR 10-61]) and the severe asthma group (37 [11.5-61]) compared to mild/moderate asthmatics (7 [0.5-37]; p < 0.05 each). Subjects reporting a history of gastro-oesophageal reflux disease (GORD) had higher LLMI values (41.5 [11.3-138] versus 13 [0-39.3], p = 0.02). There was no significant correlation between LLMI and chronic cough, BAL cell differential counts, FEV1, FEV1/FVC or body mass index (BMI). The reduced LLMI in mild/moderate asthma may be related to lower incidence of GORD. However, this was not related to the degree of airflow obstruction, obesity or airway inflammation.
    Respiratory medicine 10/2013; 108(1). DOI:10.1016/j.rmed.2013.10.005 · 3.09 Impact Factor
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    • "The lipids in macrophages are predominantly cholesteryl esters and triglycerides and are stored in cytosolic lipid droplets [2]. Although it is established that accumulation of these cytosolic lipid droplets results from increased intracellular levels of cholesterol derived from uptake of oxidized LDL [3], our previous results indicate that hypoxia may exacerbate lipid accumulation in macrophages even in the absence of lipoproteins [4]. We showed that the hypoxia-induced lipid accumulation in macrophages is a result of increased triglyceride biosynthesis and decreased â-oxidation [4], but the exact mechanism is unknown. "
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    ABSTRACT: Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
    PLoS ONE 08/2012; 7(8):e42360. DOI:10.1371/journal.pone.0042360 · 3.23 Impact Factor
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    • "In the setting of hypoxic stress, lipid metabolism is reprogrammed to suppress mitochondrial oxidation of lipidderived carbon. Specifically, hypoxia stimulates lipid storage and inhibits lipid catabolism through β-oxidation (Huss et al., 2001; Whitmer et al., 1978; Bostrom et al., 2006). "
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    ABSTRACT: Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFα subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1α (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway.
    Molecular cell 10/2010; 40(2):294-309. DOI:10.1016/j.molcel.2010.09.022 · 14.02 Impact Factor
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